HOW TO STUFF A NUCLEUS

When it comes to packing sleeping bags, it seems like there are two kinds of people: Some people meticulously squeeze out every drop of air, rolling the bag into a perfect cylinder. Others impatiently stuff the bag willy-nilly into a sack, and with occasional shoves from a helpful foot (or two), end up with a misshapen lump. This is all well and good for a sleeping bag… but how do you even begin to pack two meters of DNA1 into a single nucleus? And how does a million meters of genetic material compress into the size of a single poppyseed?2

All that makes us human is compacted into 23 pairs of these stubby, insignificant-looking things. [Image: Abogomazova, CC BY-SA 3.0]

DNA’s double helix may have been one of the greatest discoveries of the last century, but one of today’s most intriguing mysteries is the loop-ome—the 3-D architecture of the genome. Arranged into patterns of ~10,000 loops, the structure of the genome is anything but haphazard.3 Many of these loops, defined by evolutionarily conserved start and end sites, are preserved in genomes across many species.3Loops are formed, in part, by CTCF—an architectural protein that binds to DNA as well as other CTCF proteins. When two (DNA-bound) CTCF proteins also bind each other in a specific way, they can create a DNA loop by bringing together two distant sites within the genome. CTCF binds DNA at specific sites, forming loops that coordinate long-range interactions between DNA regulatory elements.4 This can facilitate transcription, if enhancers are brought close to their target promoters, but can also block gene expression by separating regulatory elements in 3D space. Further, CTCF can define boundaries of topologically associating domains (TADs) in the genome.5These TADs are like neighborhoods of clustered DNA that don’t really interact with DNA outside of their own TAD.5 Moreover, these regions are comprised of genes that are typically co-regulated, since TADs generally share similar chromatin modifications.6

Need it visualized? This perfect, cute, and transcendent example of effective scicomm says it all.

With 55,000-65,000 binding sites present across mammalian genomes,5 CTCF’s effect on gene expression is sure to impact all areas of cellular function. While complete depletion of CTCF in mice is fatal,7 human mutations in CTCF have been associated with anything from cancers8 to brain abnormalities.7 And while investigation of CTCF could lead anywhere, one of the most fascinating possibilities is its potential role in generating cell type diversity. All cells contain the same DNA, but for instance, can end up as heart cells or neurons—it all depends on which genes get expressed. Each cell type has a strictly regulated transcriptional program, which may be reflected (or instructed) by the genome structure… especially since there’s increasing evidence for cell-type-specific loop-omes.3

Somewhere in that seemingly tangled mass of DNA are distinct patterns of organization. And indeed, the consistent, deliberate architecture of the genome could just be the answer to how DNA instructs all the diversity of life. How to pack a sleeping bag might reveal one’s personality, but how to stuff a nucleus could very well define us all.